Infectious conjunctivitis is an ophthalmic disorder characterized by inflammation of the conjunctiva secondary to invasion of a microbe. Microbes are capable of causing conjunctivitis in humans include bacteria (including Mycobacteria sp), viruses, fungi, and amoebae. Current treatments for bacterial conjunctivitis consist of antibiotic drops. Because antibiotic drops are ineffective against viral conjunctivitis, treatments for such infections can only relieve symptoms. Treatments for fungi and amoeba conjunctivitis consist of a small selection of medications which lack sufficient anti-bacterial or anti-viral activity and are sometimes toxic to the ocular surface.
Diagnosis of the various causative agents such as bacteria, virus, or fungus, in infectious conjunctivitis is not economically feasible because accurate diagnosis requires sophisticated laboratory culture not easily integrated into the average healthcare practice. Because accurate diagnosis is impractical, most conjunctivitis is presumed to be bacterial without culturing and is treated with antibiotics. Antibiotic treatment is suboptimal because it is ineffective against viral or fungal conjunctivitis. In summary, there is currently no ophthalmic antimicrobial drug that has broad activity against all the causes of conjunctivitis or keratitis and can be safely used in infectious conjunctivitis or keratitis that can potentially be viral or fungal in origin.
Ophthalmic topical drug delivery is one of the important methods of application, but the existence of cornea barrier, tears' dilution and lacrimal passage's drainage effect limit the treatments and bioavailability of many topical ophthalmic preparations, especially for the posterior segment disease. In order for a high concentration in the Eyeball Vitreous, repeated intraperitoneal drug administration is necessary. However, repeated administration increases not only the patient's discomfort, but also the risk of operations and complications. On the other hand, ophthalmic drugs can be absorbed in nasal and oral cavity which increases the toxic or side effects during the treatment. Therefore for local effectiveness, many researchers want to explore a new drug carrier system to maintain the drug concentration for a longer period time, to increase effectiveness and to decrease the risk of complications and to gain the treatment goal. In recent years, many researches find that lots of slow and controlled-releasing agent like liposome and microsphere can maintain drug release for a longer time, and decrease the frequency of drug administration, reduce the drug concentration peak phenomenon, reduce the dosage and the toxicity. Biodegradable microspheres, compared to other agents, have the advantages of simple preparation, better stability and lower cost etc. Among all the drug delivery systems, only the microsphere formulations and solid implants can really result in controlled release, and microspheres formulations have the additional advantage of suspendability in a medium used as eye drops reducing the discomfort in the eyes.
Microspheres are microspherical entities formed by dissolving or dispersing drugs in excipients. They are fine and uniform particles, can encapsulate drugs with poor water-solubility, and can be used to prepare drug formulations with sustained effected or for special targets. Usually those with particle size in the range of 1-250 μm are called microspheres, and those between 10-1000 nm are called nanoparticles. Commonly used particles have the size of 200 nm to 40 μm, and those used for ocular drug-delivery have the particle size no more than 10 μm, otherwise patients will feel ocular irritation. If the particles remain in the eyes after the drug-carrying microspheres drop into eyes, the microspheres will be more suitable for sustained and controlled release. As such, preparation of particle-based pharmaceutical formulations typically has a more stringent requirement for the control of the particle size. Among others, pilocarpine, β-receptor blockers, chloramphenicol, hydrocortisone, and Amikacin have been made into such formulations.
Povidone iodine (PVP-I) is a complex of polyvinylpyrrolidone and iodine. It is also called iodophor and contains 9-12% effective iodine. It is a powerful disinfectant with a broad spectrum of applications and is strongly effective against viruses, bacteria, fungi, and mold spores. It causes little irritation on skin and has low toxicity and lasting effect, and can be used safely and easily. It basically does not cause irritation on tissue and widely used for skin and mucous membrane's disinfection, e.g., for pre-surgical cleaning and disinfection of surgical site and wound. The principle of sterilization is mainly through the release of hydrated iodine which has bactericidal effect. Povidone is hydrophilic and can carry iodine to cell membrane. When the complex arrives at the cell wall, the iodine is released and then complexes with amino acids of bacterial protein to denature it and, at the same time, oxidize the active groups of the bacteria's protoplasmic protein so that the bacteria dies rapidly. Povidone iodine is a very good bactericidal agent with no antibiotic resistance. In common use, povidone iodine's concentration is between 0.1% and 10%. Current povidone iodine preparations are in the forms of gel, suppository, cream, solution, with concentration ranging from 1% to 10%. (See Chinese Pharmacopoeia 2010 Edition). Povidone iodine eye drops have been widely used for the treatment of ocular infection basically with high concentrations of 5% with toxic effects that cannot be ignored. Grimes and others treated infected eyes repeatedly with 0.02% PVP-I eye drop which has the same germicidal effects as one with concentration of 5.0% povidone iodine but without the toxic affection and irritation. (See Grimes S R et al., Mil. Med., 1992, 157:111-113.) In order to retain a povidone iodine eye drop' sterilizing effect, but also to eliminate its toxicity to eyes, clinical operation usually use PVP-I eye drops with concentration of 0.04% to disinfect eyes with no noticeable toxicity. However, at a low concentration, povidone iodine will degrade quickly and its concentration cannot be effectively maintained at the infected site due to the tear barrier effects. Therefore, in order to reduce the toxic effect on the eyes by povidone iodine at a high concentration meanwhile maintaining its pharmaceutical effect at the infected site, it is often necessary to prepare formulations with low toxicity and long-lasting effect. Among those currently controlled release formulations used for the eyes, ocular implants and microspheres formulations are more practical. In the treatment of ocular infections, application of ocular implants in the infected sites needs assistance by a physician, thereby greatly decreasing the patients' medication compliance.
As a result of strong oxidizing potential and acidity of povidone iodine, it is difficult to prepare povidone iodine microspheres from commonly used microsphere materials. Meanwhile, however, the microparticle technologies cannot be used to prepare effective system for the slow release of povidone iodine in the eyes.